Graves' disease with pancytopenia: A rare case report

Key Clinical Message In this case report we describe a patient with Grave's disease (GD) who was first diagnosed with pancytopenia and did not have any typical symptoms of GD. His hematologic abnormalities were alleviated after treatment with an anti‐thyroid drug. Hence, in patients with pancytopenia, GD should also be considered. Abstract A variety of hematologic abnormalities can be seen in Graves' disease (GD), however; here, we describe a patient with GD and a very rare complication; pancytopenia. His hematologic abnormalities and clinical status were alleviated after treatment with an anti‐thyroid drug. Hence, in patients with pancytopenia and normal bone marrow examination, GD should also be considered.


| INTRODUCTION
Graves' disease (GD is a chronic autoimmune disorder that produces antibodies against the thyrotropin (TSH) receptors on the thyroid. 1 GD is a syndrome that is characterized by hyperthyroidism with a diffuse goiter, an eye disease that involves intra-orbital structures, and dermopathy known as pretibial myxedema. 2GD can cause a variety of symptoms such as hyperactivity, hyper defecation, weight loss with increased appetite, weakness, and polyuria. 3In about half of GD patients, the characteristic clinical hallmarks may be absent therefore other findings may help us in the diagnosis of GD. 4 Sometimes, GD may present with single-cell lineage hematological abnormalities such as neutropenia, anemia, and thrombocytopenia. 3,5But Pancytopenia due to GD is a rare complication. 5,6Although the pathogenesis of this association is not clearly fathomed, hypotheses based on immunogenic and toxic mechanisms have been considered. 7The lack of production of hematopoietic cells in the bone marrow and the increase in the immunologic destruction of mature hematopoietic cells can be considered the two main pathways leading to pancytopenia. 1

| CASE PRESENTATION
A 41-year-old man presented with fatigue and a weight loss of approximately 10 kg within 2 months.He did not take any medications except acetaminophen for his occasional headaches and had no significant medical history.He was not a smoker but had a history of alcohol consumption about twice a week.His father died due to lung cancer.There was no family history of thyroid or autoimmune disease.
On physical examination, his weight was 65 kg and his height was 182 cm.His vital signs included the following: blood pressure of 105/60 mmHg, temperature of 37.1°C, pulse rate of 90 beats/min, and respiratory rate of 15 beats/ min.
He had a depressed appearance.There was no sign of Hair or skin changes.There was no lymphadenopathy or hepatosplenomegaly, and his cardiovascular and respiratory systems examinations were unremarkable.
Bone marrow aspiration smears indicated a normocellular marrow.Megakaryocytes and their precursors were adequate in number.The erythroid and myeloid series were completely matured (Figure 2).Bone marrow biopsy showed a cellularity of about 50%.Therefore, pancytopenia was initially assumed to be caused by an immunologic mechanism or a bone marrow stem cell disorder such as immune-based.Bone marrow stem cell disorder like myelodysplastic syndrome was excluded because bone marrow was normal.While hematological aspects were being debated, the results of thyroid function tests came showing a significantly declined TSH (0.004 μIU/mL) with a raised T4 24 μg/dL (normal: 4.7-12.5)and T3 6 ng/ mL (normal: 0.8-2.3)indicating the presence of marked hyperthyroidism.
Retrospective clinical examination manifested mild diffuse goiter as well as fine tremors of the outstretched fingers.Unfortunately, these findings had been missed in the earlier clinical examinations.Later, Graves' disease was diagnosed via investigating with thyroid scanning with technetium 99 m pertechnetate, showing a diffuse rise in uptake.Treatment with methimazole (30 mg/day) was commenced.After 2 days of treatment, the platelet count and white blood cell count began to slowly rise.After 6 days, he was discharged from the hospital with acceptable improvement in his condition.He continued to take 30 mg/day of methimazole and was followed at the outpatient clinic of the hospital.After 2 weeks of treatment, TT4 and TT3 levels decreased gradually.The same dose of methimazole was continued and after 4 weeks, the clinical condition became better.Blood counts and FT4 reached normal levels after 4 and 8 weeks of treatment, respectively.Because of the risk of ATD-induced pancytopenia, he was further treated with radioiodine ablation (Iodine-131).

| DISCUSSION
In this case, the patient presented with pancytopenia and hyperthyroidism.He had no history of drug consumption or infection-related laboratory findings.A bone marrow smear ruled out the possibility of an underlying myelodysplastic syndrome.These findings suggest that hyperthyroidism can induce pancytopenia.After the improvement in the thyroid hormone levels, the blood counts were normalized promptly.Single-lineage hematologic abnormalities are more common in patients with GD but pancytopenia has been rarely described in the literature. 1,8,9Anemia has been found in 33% of GD and a patient's red blood cell mass can also increase in GD, due to both thyroid hormones' direct effects on the erythroid marrow and a rise in the production of erythropoietin.However, anemia can also be detected in hyperthyroid patients generally due to concomitant plasma volume expansion, the decline in erythrocyte lifespan, abnormal iron use, lack of iron storage, and rising need for vitamin B12 and folic acid.Any type of anemia might encounter in the course of hyperthyroidism.Normocytic anemia is the most common, while microcytic or macrocytic anemia can also occur. 10Our patient had normocytic normochromic anemia in the peripheral blood smear.He had no evidence of vitamin B12, iron deficiency, or hemolytic anemia.In bone marrow aspiration and biopsy, bone marrow cellularity and maturity were both normal, and aplastic anemia and myelodysplastic syndrome were both ruled out.
In GD, leukopenia is commonly found as a result of decreased neutrophil counts.Leukopenia can happen as a result of one of these two pathways.First granulopoiesis is reduced by a decrease in the granulocyte reserve of bone marrow, on the other hand, there is a hypothesis that destruction can happen as a result of immunologic mechanism, as antineutrophil antibodies in the serum of patients with thyrotoxicosis were detected. 5It is showed that there is a significant association between T3 levels and absolute neutrophil counts, TSH and absolute CD4 counts, T4 levels and absolute CD4 counts. 4A characteristic blood finding of GD, called Kocher's blood picture, consists of a rise in lymphocyte counts alongside a normal or marginally low white blood cell count. 11,12It has been said that low neutrophil count in thyrotoxicosis is due to a decline in the number of granulocytes in bone marrow as well as reduced circulation duration of these cells.Additionally, cross antigenicity among human TSH receptors and polynuclear neutrophils has been considered a potential cause of neutropenia in thyrotoxicosis.Abbreviations: MCHC, mean cell hemoglobin concentration; MCV, mean cell volume; T4, thyroxine; T3, triiodothyronine; TSH, thyroid stimulating hormone.
T A B L E 1 Laboratory case results.

F I G U R E 2 (A) Bone marrow aspiration smear shows normocellular marrow and normal hematopoiesis (Wright-Giemsa stain). (B) Bone marrow biopsy shows about 50%cellularity (H&E stain).
T A B L E 2 Case reports of Grave's disease presenting as pancytopenia.In the presented patient, Blood findings were compatible with Kocher's blood picture.Platelet counts are usually normal in GD.Mild immune thrombocytopenia is known to be associated with Graves' disease and alleviated with proper management.Elevating thyroid hormones result in increased destruction of the platelets as well as activation of the reticuloendothelial system resulting in a significant decline in platelets' lifespan.Also, anti-platelet antibodies were detected in Graves 'disease.Commonly platelet counts return to normal with proper management. 13ancytopenia can happen as a result of other reasons of thyrotoxicosis and not only Grave's disease.In a study, it showed that one of the underlying pathologies is that high amount of thyroid hormone in blood and its toxic effect on bone marrow cells can lead to increase in functional activity of reticuloendothelial cells, causing insufficient erythropoiesis.The sequestration of immature erythroid cells can lead to all types of anemia by dramatically increasing the intake of vitamin B12, iron, and folic acid (Table 2). 175][16] Most such cases have been associated with Graves' disease indicating that both hyperthyroidism and autoimmunity can lead to pancytopenia in GD patients.Bone marrow biopsy can be either hypercellular 14,15,16 or normocellular 7 as in our patient, and potential causes for this particular association are reduced peripheral circulation time, spleen sequestration, stem cell dysfunction, and nutritional deficiencies.Since there is improvement in blood cell counts with normalization of thyroid status, thyroid hormones most probably have a direct effect on the blood cell count decline.The main challenge for our patient was his treatment, knowing that methimazole itself can cause agranulocytosis, and regarding radioiodine ablation, there was a risk of a thyrotoxic crisis.However, the incidence of pancytopenia with thionamides is rare and the incidence of agranulocytosis with the anti-thyroid drug is 0.1%-0.5%. 18Therefore, we preferred to initially treat the patient with methimazole for 3 months and then commence radioiodine ablation.We periodically followed the patient's hematological counts during treatment with methimazole and radioiodine.As in all other reported cases, our patient's pancytopenia resolved after the correction of thyrotoxicosis.Case reports of Grave's disease whom also presented as pancytopenia have been summarized in Table 2.

| CONCLUSION
In patients with pancytopenia and normal bone marrow, GD can be considered a missed diagnosis, as patients with GD-induced pancytopenia respond well to anti-thyroid drugs.Hence, alongside following hematological parameters the main aim of treatment should be to reach a euthyroid state.

F
I G U R E 1 Peripheral blood smear shows mild anisocytosis with large platelet.Large platelet is shown with an arrow.(Wright-Giemsa stain, Magnification: 100×). 12